DRUG INTERACTION

Defination

• It is the modification of the effect of one drug (the object drug ) by the prior concomitant administration of another (precipitant drug).

• Concomitant use of several drug in presence of another drug is often necessory for achiving a set of goal or in the case when the patient is suffering from more than one disease.

• In these cases chance of drug interction coud increase.

content

• Defination

• Epidemiology

• Risk factor

• Out come of interaction

• Mechanism of interaction

a. pharmacokinetic

b. pharmacodynemic

• Case study

• Reference

Epidemiology

• In harvard medical practice study of adverse event 8% were consider to be due to drug interaction.

• US community pharmacy study revealed 4.1 % incidence of drug interaction in hospitalised patient.

• Australian study found that 4.4% of all ADR , which resulted in hospital due to interaction.

Risk factors

• Poly pharmacy

• Multiple prescribers

• Multiple pharmacies

• Genetic make up

• Specific population like e.g, females , elderly, obese, malnouresed , criticaly ill patient , trasplant recipient

• Specific illness E.g. Hepatic disease,

Renal dysfunction,

• Narrow therapeutic index drugs

Cyclosporine, Digoxin, Insulin, Lithium , Antidepressant, Warfarin

Outcomes of drug interactions

1) Loss of therapeutic effect2) Toxicity3) Unexpected increase in pharmacological activity4) Beneficial effects e.g additive & potentiation (intended)

or antagonism (unintended).5) Chemical or physical interaction

e.g I.V incompatibility in fluid or syringes mixture

Mechanisms of drug interactions

Pharmacokinetics Pharmacodynamics

Pharmacokinetics involve the effect of a drug on another drug kinetic that includes absorption ,distribution , metabolism and excretion.

Pharmacodynamics are related to the pharmacological activity of the interacting drugs E.g., synergism , antagonism, altered cellular transport effect

on the receptor site.

Pharmacokinetic interactions

1) Altered GIT absorption.

•Altered pH•Altered bacterial flora• formation of drug chelates or complexes• drug induced mucosal damage • altered GIT motility.

a) Altered pH; The non-ionized form of a drug is more lipid

soluble and more readily absorbed from GIT than the ionized form does.

Ex1., antiacids Decrease the tablet dissolution of Ketoconazole (acidic)

Ex2., H2 antagonists

Therefore, these drugs must be separated by at least 2h in the time of administration of both .

b) Altered intestinal bacterial flora ;

EX., 40% or more of the administered digoxin dose is metabolised by the intestinal flora.

Antibiotics kill a large number of the normal flora of the intestine

Increase digoxin conc. and increase its toxicity

c) Complexation or chelation;

EX1., Tetracycline interacts with iron preparations

or

Milk (Ca2+ ) Unabsorpable complex

Ex2., Antacid (aluminum or magnesium) hydroxide

Decrease absorption of ciprofloxacin by 85% due to chelation

d) Drug-induced mucosal damage.

Antineoplastic agents e.g., cyclophosphamide vincristine procarbazine

Inhibit absorptionof several drugseg., digoxin

e) Altered motility

Metoclopramide (antiemitic)

Increase absorption of cyclosporine due to the increase of stomach empting time

Increase the toxicityof cyclosporine

f) Displaced protein binding

It depends on the affinity of the drug to plasma protein. The most likely bound drugs is capable to displace others. The free drug is increased by displacement by another drug with higher affinity.

Phenytoin is a highly bound to plasma protein (90%), Tolbutamide (96%), and warfarin (99%)

Drugs that displace these agents are AspirinSulfonamidesphenylbutazone

g) Altered metabolism

The effect of one drug on the metabolism of the other is well documented. The liver is the major site of drug metabolism but other organs can also do e.g., WBC,skin,lung, and GIT.

CYP450 family is the major metabolizing enzyme in phase I (oxidation process).

Therefore, the effect of drugs on the rate of metabolism of others can involve the following examples.

E.g., Enzyme induction

A drug may induce the enzyme that is responsible for the metabolism of another drug or even itself e.g.,

Carbamazepine (antiepileptic drug ) increases its own Metabolism.

Phenytoin increases hepatic metabolism of theophyllineLeading to decrease its level Reduces its action

and Vice versa

N.B enzyme induction involves protein synthesis .Therefore, it needs time up to 3 weeks to reach a maximal effect

Eg., Enzyme inhibition;

It is the decrease of the rate of metabolism of a drug by another one . This will lead to the increase of the concentration of the target drug and leading to the increase of its toxicity .

Inhibition of the enzyme may be due to the competitionon its binding sites , so the onset of action is short may be within 24h.

When an enzyme inducer ( e.g. carbamazepine) is administered with an inhibitor (verapamil)

The effect of the inhibitor will be predominant

Ex.,Erythromycin inhibit metabolism of astemazole and terfenadine

Increase the serum conc. of the antihistaminic leading to increasing the life threatening

cardiotoxicity

EX., Omeprazole Inhibits oxidative

metabolismof diazepam

•Onset of drug interaction

It may be seconds up to weeks for example in case of enzyme induction, it needs weeks for protein synthesis, while enzyme inhibition occurs rapidly.

The onset of action of a drug may be affected by the half lives of the drugs e.g., cimitidine inhibits metabolism of theophylline.

Cimitidine has a long half life, while, theophylline has a short one.

When cimitidine is administered to a patient regimen for Theophylline, interaction takes place in one day.

First-pass metabolism:

Oral administration increases the chance for liver and GIT metabolism of drugs leading to the loss of a part of the drug dose decreasing its action. This is more clear when such drug is an enzyme inducer or inhibitor.

EX., Rifampin lowers serum con. of verapamil level by increase its first pass . Also, Rifampin induces the

hepatic metabolism of verapamil

Renal excretion:

•Active tubular secretion

It occurs in the proximal tubules. The drug combines with a specific protein to pass through the proximal tubules.

When a drug has a competitive reactivity to the protein that is responsible for active transport of another drug .This will reduce such a drug excretion increasing its con. and hence its toxicity.

EX., Probenecid ….. Decreases tubular secretion of methotrexate.

* Passive tubular reabsorption;

Excretion and reabsorption of drugs occur in the tubules By passive diffusion which is regulated by concentration and lipid solubility.

Ionized drugs are reabsorbed lower than non-ionized ones

Ex1., Sod.bicarb. Increases lithium clearance and decreases its action

Ex2., Antacids Increases salicylates clearance and decreases its action

It means alteration of the dug action without change in its serum concentration by pharmacokinetic factors.

EX., Propranolol + verapamil Synergistic or additive effect

Pharmacodynemic interaction

Additive effect : 1 + 1 =2

Synergistic effect : 1 +1 > 2

Potentiation effect : 1 + 0 =2

Antagonism : 1-1 = 0

Pharmacodynamic interactions

• Receptor interaction– Competitive– Non-competitive

• Sensitivity of receptor– Number of receptor– Affinity of receptor

• Alter neurotransmitter release /drug transportation

• Alter water/electrolyte balance

Drug-Food interactions

• Grapefruit juice and Terfenadine

• Grapefruit juice and cyclosporin

• Grapefruit juice and felodipine

• Grapefruit contains : furanocoumarin compounds that can selectively inhibit CYP3A4

PharmacogeneticsPharmacogeneticsPharmacogenomicsPharmacogenomics

Pharmacology + Genetics/Genomics

• The study of how individual’s genetic inheritance aff

ects the body’s response to drugs (efficacy & toxicity)

• The use of genetic content of humans for drug discov

ery

Variations in drug response and drug toxicity may result from

Variation in drug transporters • -P glycoprotien

Variation in diseas e modifying genes

• Apolipoprotein (APOE)

Variation in dru g metabolizin g enzymes• Cytochromes P

450

• -Thiopurine S methyltransferase

Variation in drug t argets

• -Beta2 adrenergi c receptor

• ACE• Dopamine receptor

Changes in the DNA sequence such as–Nucleotide mutation•The most frequent DNA variation found in the human genome is single nucleotide polymorphism (SNP)

–Nucleotide deletion

–Nucleotide insertion

–Gene deletion

–Gene duplication

DNA polymorphismDNA polymorphism

Common genetic polymorphism of humanCommon genetic polymorphism of humandrug metabolizing enzymesdrug metabolizing enzymes

Enzyme PM incidence Drug substrates

CYP2D6Dextromethrophanbeta-blockersAntiarrythmicsAntidepressantsNeuroleptics

Caucasians 5-10%Asians 1%

CYP2C19 Caucasians 2-5%Asians 7-23%

MephenytoinMephobarbitalHexobarbitalDiazepamOmeprazoleLansoprasole

CYP2C9 Caucasians < 1%Tolbutamide(S)-WarfarinPhenytoinNSAIDs

Caucasians & Asians 0.3%Azathioprine6-Mercaptopurine6-Thioguanine

Thiopurine S-methyltransferase

Management of an adverse interaction

Dose related events may be managed by changing the dose of the affected medicine.

• Eg.,when miconazole oral gel causes an increase in bleeding time of warfarin then redusing the warfarin dose will bring the bleeding time back into range and reduse the risk of haemorrhage

• It is important to retitrate the dose of warfarin when the course of miconazole is coumplete.

The potential severity of some interaction require immediate

Cessation of the combination.

• Eg,.the combination of erythromycin and terfenadine can produse high terfenadine level with the risk of developing Torsel de Points.

Dose spacing is appropriate for interction involving the inhibition of absorption in the GI tract .

• Eg.,avoidig the binding of ceprofloxacin by ferous salts

Case study

• Aim : Evaluation of p’kinetic drug interaction

The proposal of the study was approved by the ethical committee of the shaheed beheshti medical university.

At first questionnaries was designed for collecting data. First part of the questionnaries contain demographic data

of patients including sex and age. In the second part there was a table for writing all drugs

prescribed including drug name, dosage form, dosage amount, rout of administration and timing of the administration.

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• A total number of 116 patients of ICU ward were visited during the study and one questionnaire was filled for each visit.

• Data for total number of 567 prescriptions were recorded. The extent of occurrence and frequency of potential pharmacokinetic drug interactions were investigated based on the reference text Drug Interaction Facts published in the year 2004.

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• All of the potential pharmacokinetic drug interactions were extracted and classified in terms of mechanism, significance, onset, severity .

• Onset shows how rapidly the clinical effects of interaction can occur. This determines the urgency with which preventive measures should be instituted to avoid the consequences of the interaction.

Severity of interactions is classified in 3 categories:

Result

• A total number of 116 patients were enrolled the study with the mean age of 46(± 7) years. 65 (%56.03) patients were male and 51 (%43.97) were female.

• From 567 prescriptions, 413 pharmacokinetic interactions were identified. . Four of the most common types have shown respectively in table 1.

Table 1. The most common pharmacokinetic interactions in the studied ICU prescriptions

No. Interaction between Number in 413 cases of interactions

Percentage in 413 cases of interactions

1 Ciprofloxacin- Sucralfate 137 33.17

2 Ciprofloxacin-Magnesium sulfate

22 5.32

3 Digoxin- Metoclopramide 17 4.11

4 Theophylline- Rifampin 16 3.87

• Among the mechanisms of pharmacokinetic interactions, the most dominant type was metabolic interaction with a total percentage of %60.05.

• Table 2. Distribution of different mechanisms of the pharma-

cokinetic interactions

Mechanism Total number percentage

Metabolism 248 60.05

Absorption 158 38.26

Elimination 4 0.97

distribution 3 0.72

Table 3. Categories of drug interactions Interaction type Number of interaction Percentage

Onset

Delayed 251 61%

Rapid 162 39%

Severity

Major 72 17.43%

Moderate 335 73.61%

Minor 0 0%

Unknown 37 8.96%

Documentation

Establised 102 24.7%

Probable 166 39.95%

Suspected 109 26.39%

Unknown 37 8.96%

Significance

1 72 17.43%

2 335 73.61%

Unknown 37 8.96%

discussion

• Whenever a patient receives multiple drug therapy, the

possibility of a pharmacokinetic interaction exists. • This study shows the most prevalent pharmacokinetic

interactions in ICU may be metabolic and those related to absorption alterations (about %98.31).

• Interaction between ciprofloxacin and sucralfate, an absorption type, was the most prevalent one .

• In the ICU, nurses usually determine timing of drug administration.

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• Study showed the higher the number of drugs in prescriptions, the higher the number of interactions. Therefore, polypharmacy should be avoided as much as possible .

Reference :

• Text book of Clinical pharmacy by Parth sarthi.

• K.D.Tripathi

• Iranian journal of p’ceutical research .page 215-218,2006 by school of pharmacy shahid baneshti university of medical science and health services.

THANKS TO ALL